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The Effect of Refractive Error on Melanopsin-Driven Pupillary Responses.

ABSTRACT: Purpose:Human and animal studies suggest that light-mediated dopamine release may underlie the protective effect of time outdoors on myopia development. Melanopsin-containing retinal ganglion cells may be involved in this process by integrating ambient light exposure and regulating retinal dopamine levels. The study evaluates this potential involvement by examining whether melanopsin-driven pupillary responses are associated with adult refractive error. Methods:Subjects were 45 young adults (73% female, 24.1 ± 1.8 years) with refractive errors ranging from -6.33 D to +1.70 D. The RAPDx (Konan Medical) pupillometer measured normalized pupillary responses to three forms of square-wave light pulses alternating with darkness at 0.1 Hz: alternating long wavelength (red, peak at 608 nm) and short wavelength (blue, peak at 448 nm), followed by red only and then blue only. Results:Non-myopic subjects displayed greater pupillary constriction in the blue-only condition and slower redilation following blue light offset than subjects with myopia (P = 0.011). Pupillary responses were not significantly different between myopic and non-myopic subjects in the red-only condition (P = 0.15). More hyperopic/less myopic refractive error as a continuous variable was linearly related to larger increases in pupillary constriction in response to blue-only stimuli (r = 0.48, P = 0.001). Conclusions:Repeated light exposures to blue test stimuli resulted in an adaptation in the pupillary response (more constriction and slower redilation), presumably due to increased melanopsin-mediated input in more hyperopic/less myopic adults. This adaptive property supports a possible role for these ganglion cells in the protective effects of time outdoors on myopia development.

SUBMITTER: Mutti DO

PROVIDER: S-EPMC7594593 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The Effect of Refractive Error on Melanopsin-Driven Pupillary Responses.

Mutti Donald O DO Mulvihill Shane P SP Orr Danielle J DJ Shorter Patrick D PD Hartwick Andrew T E ATE

Investigative ophthalmology & visual science 20201001 12

<h4>Purpose</h4>Human and animal studies suggest that light-mediated dopamine release may underlie the protective effect of time outdoors on myopia development. Melanopsin-containing retinal ganglion cells may be involved in this process by integrating ambient light exposure and regulating retinal dopamine levels. The study evaluates this potential involvement by examining whether melanopsin-driven pupillary responses are associated with adult refractive error.<h4>Methods</h4>Subjects were 45 yo ...[more]

PMID: 33091116

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Project description:Myopia, or nearsightedness, is the most common form of refractive abnormality and is characterized by excessive ocular elongation in relation to ocular power. Retinal neurotransmitter signaling, including dopamine, is implicated in myopic ocular growth, but the visual pathways that initiate and sustain myopia remain unclear. Melanopsin-expressing retinal ganglion cells (mRGCs), which detect light, are important for visual function, and have connections with retinal dopamine cells. Here, we investigated how mRGCs influence normal and myopic refractive development using two mutant mouse models: Opn4-/- mice that lack functional melanopsin photopigments and intrinsic mRGC responses but still receive other photoreceptor-mediated input to these cells; and Opn4DTA/DTA mice that lack intrinsic and photoreceptor-mediated mRGC responses due to mRGC cell death. In mice with intact vision or form-deprivation, we measured refractive error, ocular properties including axial length and corneal curvature, and the levels of retinal dopamine and its primary metabolite, L-3,4-dihydroxyphenylalanine (DOPAC). Myopia was measured as a myopic shift, or the difference in refractive error between the form-deprived and contralateral eyes. We found that Opn4-/- mice had altered normal refractive development compared to Opn4+/+ wildtype mice, starting ∼4D more myopic but developing ∼2D greater hyperopia by 16 weeks of age. Consistent with hyperopia at older ages, 16 week-old Opn4-/- mice also had shorter eyes compared to Opn4+/+ mice (3.34 vs 3.42 mm). Opn4DTA/DTA mice, however, were more hyperopic than both Opn4+/+ and Opn4-/- mice across development ending with even shorter axial lengths. Despite these differences, both Opn4-/- and Opn4DTA/DTA mice had ∼2D greater myopic shifts in response to form-deprivation compared to Opn4+/+ mice. Furthermore, when vision was intact, dopamine and DOPAC levels were similar between Opn4-/- and Opn4+/+ mice, but higher in Opn4DTA/DTA mice, which differed with age. However, form-deprivation reduced retinal dopamine and DOAPC by ∼20% in Opn4-/- compared to Opn4+/+ mice but did not affect retinal dopamine and DOPAC in Opn4DTA/DTA mice. Lastly, systemically treating Opn4-/- mice with the dopamine precursor L-DOPA reduced their form-deprivation myopia by half compared to non-treated mice. Collectively our findings show that disruption of retinal melanopsin signaling alters the rate and magnitude of normal refractive development, yields greater susceptibility to form-deprivation myopia, and changes dopamine signaling. Our results suggest that mRGCs participate in the eye's response to myopigenic stimuli, acting partly through dopaminergic mechanisms, and provide a potential therapeutic target underling myopia progression. We conclude that proper mRGC function is necessary for correct refractive development and protection from myopia progression.

Project description:PURPOSE:The intrinsically photosensitive retinal ganglion cells (ipRGCs) signal environmental light, control pupil size and entrain circadian rhythm. There is speculation that ipRGCs may be involved in the protective effects of light exposure in myopia. Here, the ipRGC-driven pupil response was evaluated in children and examined with light exposure and refractive error. METHODS:Children ages 5-15 years participated. Subjects wore an actigraph device prior to the lab visit for objective measures of light exposure and sleep. For pupillometry, the left eye was dilated and presented with stimuli, and the consensual pupil response was measured in the right eye. Pupil measurements were preceded by 5 min dark adaptation. In Experiment 1 (n = 14), 1 s long wavelength light ('red,' 651 nm, 167 cd m-2 ) and 10 increasing intensities of 1 s short wavelength light ('blue,' 456 nm, 0.167-167 cd m-2 ) were presented with a 60 s interstimulus interval. A piecewise two-segment regression was fit to the stimulus response function to determine the functional melanopsin threshold. Pupil responses were analysed with light exposure over the previous 24 h. For Experiment 2 (n = 42), three 1 s red and three 1 s blue alternating stimuli were presented with a 60 s interstimulus interval. Following an additional 5-min dark adaption, the experiment was repeated. Pupil metrics included peak constriction, the 6 s and 30 s post-illumination response (PIPR), early and late area under the curve (AUC). Following pupil measurements, cycloplegic refractive error and axial length were measured. RESULTS:For Experiment 1, PIPR metrics demonstrated a graded response to increasing intensity blue stimuli, with a mean functional melanopsin threshold of 6.2 ± 4.5 cd m-2 (range: 0.84-16.7 cd m-2 ). The 6 s PIPR and early AUC were associated with 24-h light exposure for high intensity stimuli (33.3 and 83.3 cd m-2 , p < 0.005 for both). For Experiment 2, there were no associations between pupil metrics and refractive error. The 6 s PIPR and early AUC to blue stimuli were significantly increased for Trial 2 compared to Trial 1. CONCLUSIONS:The ipRGC-driven pupil responses in children were robust and similar to responses previously measured in an adult population. The 6 s PIPR and early AUC to high intensity blue stimuli were associated with previous light exposure. There were no associations between the ipRGC-driven pupil response and refractive status in this cohort.

Project description:Accommodative esotropia (AE) is a convergent deviation due to an excess of the convergence linked to the innervational stimulus for accommodation and it is usually associated to the presence of hyperopia. The development of hyperopia over time has been widely described but the lack of comparative analysis among accommodative esotropia subtypes, does not allow to verify the existence of different developmental patterns. In this study we aimed to describe the long term changes of refractive error in patients affected by accommodative esotropia as a function of the strabismus type: refractive (RAE), non-refractive (NRAE) and partially accommodative esotropia (PAE). The medical records of 66 patients (24 RAE, 22 PAE, 20 NRAE), who wore the full correction of their cycloplegic refraction error during the entire follow up period, were retrospectively reviewed. Mean outcome was the analysis of the variations, among groups, of refractive error over time; differences between mild (≤3.00D) and high (≥5.00D) hyperopia, effects of amblyopia and relationship with AC/A ratio were also investigated. All patients were followed up from approximately 4 years of age to 20, with mean follow up of 16.06±0.29 years. Our results described similar non-linear trend of refractive error development among groups. The initial increase of hyperopia (up to 7-8 years) was followed by a decreasing trend persisting up to adulthood (approximately 20 years of age). During this period, spherical equivalent decreased at a lower mean annual rate in patients affected by RAE (-0.07D) compared to other groups (NRAE -0.11D, p = 0.003 and PAE 0.13D, p = 0.002). In all groups, however, significant amount of hyperopia was found at last examination; indeed the observed difference in SE values from baseline to the end of follow up, was not significant (RAE: +0.27D, 95% C.I. -0.49 to +1.04D, p = 0.472; PAE: -0.69D, 95% C.I. -1.67 to +0.28D, p = 0.154; NRAE: -0.39D, 95% C.I. -1.11 to +0.34D, p = 0.278). AC/A ratio, amblyopia and amount of initial hyperopia appeared to have no significant role in longitudinal change of the refractive error. In conclusion, this study provides a complete overview, from childhood to adulthood, of refractive error development in different form of accommodative esotropia.

Dataset Information

The Effect of Refractive Error on Melanopsin-Driven Pupillary Responses.

Publications

The Effect of Refractive Error on Melanopsin-Driven Pupillary Responses.

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